The social environment has a clear and profound impact on human health and well being. Chronic social stress and reduced access to social support are predictive of a number of adverse health outcomes, including cardiovascular disease and diabetes. Indeed, evidence suggests that social stress is linked to life expectancy itself: poor social integration, for example, has been estimated as a risk factor for mortality on the scale of familiar health risks like smoking and obesity. However, despite keen interest in social stress as a human health concern, the mechanistic relationships linking social stress to its impact on the body are still poorly understood, particularly on the level of the genome. The goal of the proposed work is to address this gap by investigating how dominance rank in female rhesus macaques influences genome regulation. Dominance status in macaques is an excellent model for human social stress: the natural hierarchical organization of macaque social groups is characterized by increased rates of harassment and threats directed towards lower ranking group members, which are reflected in rank-related stress physiology. Additionally, dominance rank assignments can be experimentally imposed in this species by altering group membership. Thus, an individual's exposure to social stress can also be manipulated, yielding an experimental system for investigating the effects of social stress on the genome that is directly translatable to humans, but that is practically and ethically impossible in humans themselves. The proposed study will take advantage of this system to investigate how dominance status and differential exposure to social stress influence gene expression in immune cells in the peripheral blood. This relationship will be investigated in four different cell types that play unique roles i the immune system, as well as under both day-to-day conditions and in response to stimulation by compounds that mimic disease infection. The project will also investigate the contribution of DNA methylation, an important mark that changes the structure of DNA without altering its sequence and that is known to respond to environmental context, to social status- related gene expression variation. Importantly, the study design will include a mid-study intervention to systematically alter the dominance rank positions of each individual in the study. This approach both permits the identification of genes that are causally influenced by exposure to social stress, and also permits investigation of whether an individual's social stress history has a long-term impact on the genome even after this stress has been alleviated. Together, these efforts will illustrate how social stress changes gene expression in an important animal model for human social stress, including how stress mitigation might offset the physiological costs of prior stress and how increased stress may alter individual vulnerability to disease. PUBLIC HEALTH RELEVANCE: The social environment has a clear and profound impact on human health and wellbeing, and can impact disease susceptibility as well as mortality risk itself. This project uses a nonhuman primate model for human social stress, the rhesus macaque, to investigate the impact of social stress on the genome. The results of this project will contribute to understanding how social stress influences disease susceptibility, and whether alleviation of social stress can help eliminate these effects.